0 [5.7-15.1] ng/ ml compared with obese patients 18.8 [12.9-24.2] ng/ml (p<0.0000001) independently of liver complications. In alcoholic patients 40.2% had a steatohepatitis and 20.6% a bridging fibrosis. The levels of 25-OH vitamin D were decreased in patients with steatohepatitis or

with bridging fibrosis but its low level was independently associated only with steatohepatitis (6.5 [4.5-8.0] vs 12.0 [6.6-18.4] ng/ml, p=0.000003). In morbidly obese patients, 20.6% had a steatohepatitis, 28.9% a “moderate” fibrosis (F≥2 according to the NASH CRNSS) and 4.3% a bridging fibrosis. The 25-OH vitamin D level decreased with “moderate” fibrosis (15.9 [11.1-23.5] vs 19.6 [13.7-24.7] MAPK Inhibitor Library in vivo ng/ml, P=0.02) but not with bridging fibrosis and not with NASH. Stages of fibrosis were independently associated with steatohepatitis in alcoholic and obese patients, respectively, but not with a vitamin D deficiency. Conclusion: Alcoholic patients were frequently deficient in 25-OH vitamin D. This was highly more frequent compared

to morbidly obese patients. In alcoholic patients, low levels of 25-OH vitamin D were associated with the bridging fibrosis and independently associated with the presence of alcoholic steatohepatitis. The role of vitamin D in the evolution of fibrosis could be indirect through the severity of Selleck HM781-36B the inflammation. In morbidly obese patients, these associations were not found. Vitamin D supplementation in alcoholic patients should be tested in clinical trials to determine if it is possible to prevent or reduce Rucaparib research buy the severity of liver histology

and mortality. Disclosures: The following people have nothing to disclose: Clémence M. Canivet, Rodolphe Anty, Stephanie Patouraux, Antonio Iannelli, Patricia Panaia-Ferrari, Imed Ben Amor, Anne-Sophie Schneck, Marie-Christine M. Saint-Paul, Jean Gugenheim, Philippe Gual, Albert Tran Background and Aims: Several metabolic disorders, such as type 2 diabetes (T2DM), obesity, and hepatic steatosis, are associated with liver cirrhosis (LC) and development of hepato-cellular carcinoma (HCC). New genetic loci that contribute to the development of T2DM have been identified by genome-wide association studies. The aim of this study was to examine the association between T2DM susceptibility loci and liver disease progression in Japanese patients with T2DM.

6A). It is noteworthy that in the three woodchucks that received IL-12 only, a decrease of wIL-10 and wPD-L1 was observed, and in two of these animals this was associated with an increase in IFN-γ expression (Fig. 6A). This result suggests ABT-263 mw that the combination of IL-12 treatment and block of Treg activity may cause/induce/have a detrimental effect. The expression

of Class I, β2-m, CD3, and CD8 molecules, however, remained unchanged in all animals (Supporting Fig. 3A). Untreated control woodchucks had no changes in the expression of these molecules (Supporting Fig. 3B), indicating that the increase in the immunosuppressive environment of the liver was due to the applied treatment. In chronic hepatitis B the failure to mount an efficient immune response against viral antigens allows continuing viral replication and progression of liver damage. T-cell function is particularly affected in this condition. The mechanism underlying impaired T-cell reactivity is not fully understood. Immunotherapy of chronic HBV infection aims at activating antiviral

T-cell immunity to promote seroconversion and long-lasting control of viral replication. In a previous study we treated woodchucks with chronic WHV infection with a gene transfer vector to express intrahepatically the immunostimulatory cytokine IL-12 under the control of an inducible promoter.18 Idelalisib chemical structure We observed that the induction of IL-12 expression resulted in a significant reduction of viral load and find more stimulation of specific anti-WHV immune response. More important, the activation of antiviral immunity was associated with a reduction of WHV covalently closed circular DNA (cccDNA) forms from the liver that are mainly responsible for the maintenance of persistent viral infection. However, the decrease in viral load was only observed in woodchucks with viremias lower than 1010 vg/mL. Woodchucks with higher viremia did not respond to treatment, and surprisingly, at the end of IL-12 administration hepatic expression of FoxP3 was significantly increased, whereas in the responder

animals FoxP3 expression was clearly reduced. Further analysis showed that peripheral blood lymphocytes obtained from woodchucks with high viral load failed to respond to IL-12 stimulation. In the present study we found that the frequency of Treg in liver of WHV chronically infected woodchucks was higher than that observed in uninfected animals. The increase in hepatic Treg was accompanied by significantly higher expression of antiinflammatory cytokines such as TGF-β1 and IL-10, and immunosuppressive molecules such as PD-1 and PD-L1. Thus, similar to chronic HBV infection, persistent infection in WHV infection is associated with a strong immunosuppressive environment within the liver.

Libert – Employment: Gilead Sciences Christiane Stern – Employment: Gilead Sciences Patrick Marcellin – Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Boehringer, Pfizer, Abbott, Alios BioPharma; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen-Tibotec, Cisplatin manufacturer MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead,

BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Abbott The following people have nothing to disclose: Denis Ouzan, Thierry Fontanges, Jean Didier Grange, Jean françois D. Cadranel Background/Aims: Liver stiffness (LS) values using PARP inhibitor transient elastography provides accurate assessment of liver fibrosis in patients with chronic liver disease. The influence of antiviral treatment using entecavir (ETV) on LS values was assessed in patients with chronic hepatitis B (CHB). Methods: One hundred and twenty-one NUC-naïve

patients with CHB who completed 3-year ETV treatment at the end of follow-up (April 201 3) were evaluated. LS was measured at the start and completion Vasopressin Receptor of the 3-year ETV treatment. The aim of this study was to evaluate the change in LS value under ETV therapy, and the presence of a decrease in LS value >1 kPa from the baseline. Results: The mean baseline LS value of the patients was 1 8.0 kPa. During the 3-year ETV treatment, the mean LS values decreased significantly from 18.0 to

9.3 kPa (P<0.001). In univariate analyses, the absence of diabetes mellitus, higher HBV DNA level, normalization of alanine aminotransferase (ALT) during the study period, and higher baseline LS values were associated with a LS decrease in LS values >1 kPa (all P<0.05). Together with ALT normalization, multivariate analysis identified higher baseline LS values as an independent predictor of a decrease of LS values >1 kPa (P<0.001; hazard ratio [HR], 1.235; 95% confidence interval [CI], 1.104-1.382). Using the optimal cutoff baseline LS value of 10 kPa (area under receiver operating characteristic curve=0.835; 95% CI, 0.732-0.937, P<0.001; sensitivity 76.5%; specificity, 73.

A number of stimuli modulate hepcidin expression to influence systemic iron balance. Erythropoietic demand and hypoxia down-regulate hepcidin transcription to increase iron availability, whereas iron, inflammatory cytokines, and endoplasmic reticulum stress up-regulate hepcidin transcription

to decrease iron availability.1, 3-7 The specific signaling pathways mediating hepcidin transcription in response to these stimuli are increasingly being elucidated. Inflammatory cytokines stimulate hepcidin transcription by way of the signal transducer and activator of transcription 3 (STAT3) signaling pathway, whereas iron stimulates hepcidin transcription by way of the bone morphogenetic protein (BMP)-SMAD signaling pathway (reviewed1). BMPs Selleckchem Mitomycin C belong to the transforming growth factor-beta (TGF-β) superfamily of ligands and are involved in a myriad of cellular and systemic functions during embryonic and adult life (reviewed8). BMPs form a signaling complex with type I and type II serine threonine kinase receptors, leading to phosphorylation of intracellular SMAD1, SMAD5, and SMAD8 proteins. These P-SMAD1/5/8 proteins form a complex with SMAD4 and translocate to the nucleus to modulate transcription of target genes such as ID1

and SMAD7.9, 10 Hepcidin is also a target transcript directly up-regulated by the BMP signaling pathway (reviewed in1). The central importance Proteases inhibitor of the BMP-SMAD signaling pathway in hepcidin regulation and iron metabolism in vivo is demonstrated by the fact that mutations in the genes encoding the BMP coreceptor hemojuvelin,11, 12 the intracellular signaling molecule

SMAD4,13 and the ligand BMP69, 14 each result in decreased hepcidin expression and iron overload. Furthermore, pharmacologic modulators of the BMP-SMAD signaling pathway regulate hepcidin expression and systemic iron balance in mice.9, 15, 16 Notably, the molecular mechanisms by which iron is sensed to induce the BMP-SMAD pathway are not fully understood. Nintedanib (BIBF 1120) Both circulating and tissue iron have been suggested to regulate hepcidin expression. Whether they exert independent effects through the BMP-SMAD pathway and/or involve additional pathways is unclear. For example, although liver iron content (LIC) is correlated with hepatic Bmp6 messenger RNA (mRNA) levels in mice,17-19 suggesting that tissue iron levels regulate BMP-SMAD pathway activity by regulating ligand expression, it is unknown whether circulating iron levels also regulate hepatic BMP6 mRNA, or whether circulating iron sensitizes hepatocytes to increase SMAD1/5/8 phosphorylation in response to tonic BMP6 levels.

, MD (Governing Board, Program Evaluation Committee, Scientific Program Committee, Abstract Reviewer) Nothing to disclose Dawson, Paul, MD (Abstract Reviewer) Consulting: GlaxoSmithKline, Isis Pharmaceuticals, Lumena Pharmaceuticals Stock: XenoPort, Inc. Deal, Julie (Staff) Stock: Bristol-Myers Squibb Delgado-Borrego, Aymin, MD (Program Evaluation Committee) Nothing to disclose DeLeve, Laurie D., MD, PhD (Abstract Reviewer) Advisory Board: Pfizer, Takeda, Bristol-Myers Squibb Di Bisceglie, Nutlin-3a cost Adrian M., MD, FACP (Governing Board, Scientific

Program Committee) Advisory Board: Gilead, Data Safety Monitoring Board, Bayer, Novartis Grants/Research Support: AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Transgene, Vertex, Alpha-1 Foundation Royalties: Section Editor on Hepatitis C, UpToDate Diaz, Susan M., PA-C, MPAS (Surgery and Liver Transplantation Committee) Nothing to disclose Dickson, Rolland C., MD (Education Committee, Abstract Reviewer) Advisory Board: Bristol-Myers Squibb, Cowen and Associates Grants/Research Support: Gilead, Roche, Tibotec, Vertex Scientific Consultant: Biotest Speaking JNK inhibitor and Teaching: Gilead Diehl, Anna Mae, MD (Abstract

Reviewer) Consulting: Roche Grants/Research Support: Gilead, Genfit Dieterich, Douglas, MD (Abstract Reviewer) Consulting: Gilead, Bristol-Myers Squibb Advisory Board: Merck, Idenix, Janssen Dolganiuc, Angela, MD (Abstract

Reviewer) Nothing to disclose Doo, Edward, MD (Abstract Reviewer) Nothing to disclose Echard, Steven (Staff) Nothing to disclose Eggers, Carol A., MSN, FNP (Program Evaluation Committee) Nothing to disclose Eghtesad, Bijan, MD (Surgery and Liver Transplantation Committee) Nothing to disclose Ekong, Udeme D., MD (Abstract Reviewer) Nothing to disclose El-Serag, Hashem B., MD (Abstract Reviewer) Nothing to disclose Emerick, Karan M., MD (Abstract Reviewer) Nothing to disclose Emond, Jean C., MD (Abstract Reviewer) Nothing to disclose Fallon, Michael B., MD (Abstract Reviewer) Grants/Research Support: Bayer-Onyx, Eaisi, Gilead, Grifolis Feld, Jordan J., MD (Abstract Reviewer) Advisory Board: Idenix, Merck, Janssen, Gilead, AbbVie, Merck, Theravance, Bristol-Myers Squibb Grants/Research Support: AbbVie, Boehringer Ingelheim, Bupivacaine Janssen, Gilead, Merck Feldstein, Ariel E., MD (Abstract Reviewer) Nothing to disclose Feng, Sandy, MD, PhD (Abstract Reviewer) Nothing to disclose Fenkel, Jonathan M., MD (Abstract Reviewer) Consulting: Gilead, Janssen Fiel, Maria Isabel, MD (Education Committee) Leadership: HEPATOLOGY Speaking and Teaching: Richmond University Hospital Grants/Research Support: P20 Mini Center, RO1 Detection of liver fibrosis, HCC in non-cirrhotic liver Expert Testimony: Fowler White Burnett, Kopff, Nardelli & Dopf, Bailly and McMillan McCormick Fitzpatrick Firpi, Roberto J.

Tissue sampling results were compared to final diagnoses, based on the following in decreasing priority: surgical findings/pathology, EUS or ERCP sampling www.selleckchem.com/products/pifithrin-alpha.html when malignant, and long-term clinical follow-up. Results: Of the 77 patients providing study consent, 26 were excluded due to: (a) ERCP not performed after EUS-FNA provided onsite diagnosis, mass appeared resectable, and referred for expedited surgery (n = 14), (b) biliary stricture not present on ERCP (stones or other cause of jaundice) (n = 8), (c)

EUS-FNA provided diagnosis in patient with patent biliary stent (n = 1), (d) ERCP not performed after EUS revealed no obstruction (suspected hepatic etiology) (n = 3). Final diagnoses in the remaining 51 patients were: pancreatic cancer (n = 34), bile duct cancer

(n = 14), and inflammatory stricture or chronic pancreatitis (n = 3). Diagnoses were based ACP-196 manufacturer on surgery (n = 13), malignancy on EUS or ERCP sampling (n = 37), and long-term follow-up (n = 1). EUS-FNA was superior to ERCP sampling overall and for pancreatic masses (Table), and similar to ERCP for biliary masses and indeterminate strictures (defined as obstructive jaundice without visible mass on pre-procedure CT / MRI). EUS-FNA yielded malignant diagnoses without complications in all cholangiocarcinoma patients with positive ERCP tissue sampling results, although two were from FNA of distant sites (lymph node, liver Gefitinib mw lesion). Conclusion: EUS-FNA is superior to ERCP sampling for establishing diagnoses in suspected malignant biliary obstruction, and particularly for pancreatic masses. EUS-FNA appears equivalent to ERCP for tissue diagnoses in patients with biliary tumors and indeterminate strictures. Given the overall superior performance characteristics of EUS-FNA, we believe EUS should be performed prior to ERCP in all patients with suspected malignant biliary obstruction. Combining

EUS / ERCP at one session may maximize diagnostic and therapeutic benefits.   Sensitivity Accuracy EUS-FNA ERCP p-value EUS-FNA ERCP p-value OVERALL (n = 51) 94% 50% 0.0001 94% 53% 0.0001 Pancreatic mass (n = 36) 100% 38% 0.0001 100% 42% 0.0001 Biliary mass or stricture < n = 15) 79% 79% NS 80% 80% NS Indeterminate stricture (n = 15) 80% 67% NS 80% 67% NS "
“Defects in natural killer (NK) cell functions are necessary for tumor immune escape, but their underlying regulatory mechanisms in human cancers remain largely unknown. Here we show, in detailed studies of NK cells in 294 untreated patients with hepatocellular carcinoma (HCC), that accumulation of functional NK cells in HCC tissues could predict improved survival of patients. However, in patients with advanced-stage HCC, NK cells were significantly decreased in number with impaired tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ) production.

The study protocol was approved by the Human Ethics Review Committee of the institution. Blood samples were frozen at −80°C within 4 hours of collection and were not thawed until used for testing. Anti-HCV, HCV RNA, HCV genotype, and aa substitutions of the HCV-1b core region were assayed using stored frozen sera. HCV genotype was determined by PCR using a mixed

primer set derived from nucleotide sequences of the NS5 region.24 HCV RNA quantitative Nutlin-3a analysis was measured by branched DNA assay v. 2.0 (Chiron), AMPLICOR GT HCV Monitor v. 2.0 using the 10-fold dilution method (Roche Molecular Systems, Pleasanton, CA), or COBAS TaqMan HCV test (Roche Diagnostics, Tokyo, Japan). High viral load of viremia levels was defined as branched DNA

assay ≥1.0 Meq/mL, AMPLICOR GT HCV Monitor ≥100 × 103 IU/mL, or COBAS TaqMan HCV test ≥5.0 log IU/mL. Low viral load was defined as branched DNA assay <1.0 Meq/mL, AMPLICOR GT HCV Monitor <100 × 103 IU/mL, or COBAS TaqMan HCV test <5.0 log IU/mL. In the present study, aa substitutions of the core region of HCV-1b were analyzed by direct sequencing. HCV RNA was extracted from serum samples selleck products and reverse transcribed with random primer and MMLV reverse transcriptase (Takara Syuzo, Tokyo, Japan). Nucleic acids of the core region were amplified by nested PCR using the following primers. The first-round PCR was performed with CE1 (sense, 5′-GTC TGC GGA ACC GGT GAG TA-3′, nucleotides: 134-153) and CE2 (antisense, 5′-GAC GTG GCG TCG TAT TGT CG-3′, nucleotides: 1096-1115) primers, and the second-round PCR with CC9 (sense, 5′-ACT GCT AGC CGA GTA GTG TT-3′, nucleotides: 234-253) and CE6 (antisense, 5′-GGA GCA GTC GTT CGT GAC AT-3′, nucleotides: 934-953) primers. All samples were initially denatured Bupivacaine at 95°C for 2 minutes. The 35 cycles of amplification were set as follows: denaturation for 30 seconds at 95°C, annealing of primers for 30 seconds at 55°C, and extension for 1 minute at 72°C with an additional 7 minutes for extension. Then 1 μL of

the first PCR product was transferred to the second PCR reaction. Other conditions for the second PCR were the same as the first PCR, except that the second PCR primers were used instead of the first PCR primers. The amplified PCR products were purified by the QIA quick PCR purification kit (Qiagen, Tokyo, Japan) after agarose gel electrophoresis and then used for direct sequencing. Dideoxynucleotide termination sequencing was performed with the Big Dye Deoxy Terminator Cycle Sequencing kit (Perkin-Elmer, Tokyo, Japan). With the use of HCV-J (accession no. D90208) as a reference,25 the dominant sequence of 1-191 aa in the core protein of HCV-1b was determined by direct sequencing and then compared with the consensus sequence constructed on 50 clinical samples to detect substitutions at aa 70 of arginine (Arg70) or glutamine/histidine (Gln70/His70) and aa 91 of leucine (Leu91) or methionine (Met91).

However,

because most studies have relied on population surveys, liver histology was not evaluated, and the possible effects of coffee/caffeine on liver fibrosis had to be indirectly assessed. The distinction between anti-fibrogenic effects and protection against decompensation is important in understanding the underlying beneficial mechanism. With complete liver biopsy data on all 177 patients, across the spectrum of liver fibrosis, the data from this study suggest that the beneficial effect of caffeine is mediated through reduced rate of progression of fibrosis. However, the lack of association between caffeine intake and hepatic inflammation suggests that, rather than reducing fibrosis by minimizing ongoing inflammation, the protective effect of caffeine may be mediated through a direct anti-fibrogenic mechanism Recent in vitro data suggest possible mechanisms by which coffee or caffeine may affect liver disease and specifically selleck chemical hepatic fibrogenesis. Studies in mice and rats as well as human hepatoma cell lines have shown that coffee and some of its major components (caffeine, cafestol, and kahweol) alter

expression and Compound Library purchase activity of enzymes involved in xenobiotic metabolisms.25–28 Inhibition of phase I enzymes and up-regulation of phase II enzymes such as glutathione-S-transferase have been reported, both of which would favor reduced accumulation of toxic metabolites within hepatocytes.27 Pretreatment with cafestol and kahweol protected mice from carbon tetrachloride hepatotoxicity by inhibiting cytochrome CYP 2E1, the enzyme responsible for carbon tetrachloride bioactivation.29 With respect to caffeine specifically, Gressner and colleagues30 recently reported that caffeine inhibits expression of connective tissue growth factor (CTGF) by interfering with transforming growth factor beta (TGFβ) signaling through the SMAD pathway.30 Caffeine was also found to up-regulate peroxisome proliferator-activated receptor gamma (PPARγ) levels, which further reduce CTGF buy Idelalisib expression. Although these results from primary cell culture

clearly need in vivo confirmation, inhibition of the transforming growth factor beta pathway is an attractive explanation for anti-fibrogenic effects attributed to caffeine. It is important to consider potential confounding factors when interpreting the data from this study. The study was cross-sectional in nature, and caffeine consumption was estimated at the time of liver biopsy, despite the fact that any protective effect would likely occur over many years. Patients consuming the greatest amount of caffeine had less fibrosis on biopsy. Although it is tempting to conclude that caffeine has a protective effect on fibrogenesis, other explanations are also possible. Patients with more advanced liver fibrosis may have reduced their caffeine intake because of a presumption that caffeine may not be good for their health.

“
“The southern right whale’s (Eubalaena australis) demography, occurrence, habitat use, and behavior off South Africa are known predominantly from an ongoing aerial survey data set that started in 1971. The fixed timeframes of these surveys and their geographical bias towards south coast nursery areas have constrained our knowledge about the right whale’s seasonal distribution elsewhere. We present shore-based observations and tracking of right whales at Saldanha Bay on the west coast (2001–2003) that reveal a near year-round presence and strongly nearshore

distribution. With seasonal progression from winter FDA-approved Drug Library clinical trial to summer we observed a gradual increase in sighting rate, reduction in swimming speed, less directionality of movement, an increase in group size, and more surface active groups. The area appears to be important for feeding and socializing but not as a calving or nursery area. Individual transits between the south and west coasts, bidirectional alongshore movements, and extended seasonal presence may

all be indicative of reoccupation of their former range along the west coast. This is important given the increasing ship traffic at Saldanha Bay, the rapid expansion of the region’s oil and gas industry, and the known vulnerability of the closely related North Atlantic right whale (E. glacialis) to ship strikes. “
“This study is part of an on-going effort to evaluate and monitor find more river dolphin populations in South America. It comprises the largest initiative to estimate population size and densities of Inia and Sotalia dolphins using statistically robust and standardized tuclazepam methods. From May 2006 to August 2007, seven visual surveys were conducted in selected large rivers of Bolivia, Colombia, Brazil, Ecuador, Peru, and Venezuela in the Amazon and Orinoco river basins. Population sizes of Inia and Sotalia were estimated for different habitats (main river, tributary,

lake, island, confluence, and channel). A total of 291 line and 890 strip transects were conducted, covering a distance of 2,704 linear kilometers. We observed 778 Inia geoffrensis, 1,323 Inia boliviensis, and 764 Sotalia fluviatilis. High-density areas were identified (within 200 m from the river banks, confluences, and lakes) and we propose that these constitute critical habitat for river dolphins. High densities of river dolphins seem to coincide with well-managed freshwater protected areas and should be considered as hot spots for river dolphins in South America. “
“Humpbacks whales (Megaptera novaeangliae) have shown a remarkable recovery in the North Pacific, raising concerns regarding their impact on marine communities. In Southeast Alaska, humpbacks feed heavily on euphausiids; however, it remains unclear whether they target immature individuals despite evidence that they do so elsewhere.

All patients participated in either a sparse population-pharmacokinetic (PK) cohort or in an optional intensive-PK cohort, which involved a more intensive schedule of sample collection. Patients who participated in the population-PK cohort were stratified based on HCV genotype (i.e., 1a versus other genotype 1 subtypes). Plasma concentrations of vaniprevir were determined GS1101 using liquid-liquid extraction, followed by high-performance liquid chromatography/tandem mass

spectrometry analysis. The lower limit of quantitation (LOQ) for the plasma assay was 1 ng/mL (1.32 nM) and the linear calibration range was 1-1,000 ng/mL. Sparse population PK samples were collected on selected days up to week 72. In addition, samples were also collected at multiple time points over the 12- or 24-hour dosing period for the subset of patients (∼4-8 patients per treatment group) included in the intensive-PK cohort. For all patients, the concentration

of drug in the plasma at 2 hours after dose and the trough concentration of drug in the plasma (Ctrough: concentration of drug in the plasma at 12 hours after dose for BID regimens and concentration of drug in the plasma at 24 hours after dose [C24h] for QD regimens) were assessed. The following additional plasma PK parameters were assessed for the intensive-PK cohort: area under the plasma-concentration versus time curve (AUC0-12h check details for the BID regimens and AUC0-24h for the QD regimens), time to reach maximum concentration (Cmax) (Tmax), and accumulation ratio, as appropriate. The accumulation of vaniprevir was determined by calculating the ratio of the PK parameter value (i.e., AUC, Cmax, and Ctrough) on days 28 and 1. WinNonlin (Pharsight Corporation, Mountain

View, CA) was used to determine PK parameters. The primary efficacy endpoint was the proportion of patients achieving RVR, defined as plasma HCV RNA below the limit of detection (LOD) at week 4. Exploratory efficacy endpoints included the proportion of patients achieving EVR (defined as plasma HCV RNA below the LOD at week 12) and the proportion of patients achieving SVR GNA12 (defined as plasma HCV RNA below the LOD 24 weeks after completing treatment with Peg-IFN and RBV). The per-protocol (PP) population was predefined as the primary efficacy-analysis population. This excluded patients who had important deviations from the protocol, such as those taking prohibited medications or who fell below predetermined levels of compliance required for each component of the treatment. Only patients with HCV RNA results at week 4 were included in the analysis of RVR using the predefined missing primary data approach of data as observed (i.e., missing data were not replaced).